Tachyarrhythmias seen clinically and in experimental animal preparations usually involve regions of slow conduction and preferentially oriented lines of block within the reentrant circuit. These arrhythmias arise in regions of the myocardium bordering an infarct with significant changes in tissue fiber structure caused by healing or remodeling. The major factors contributing to the sudden onset of these arrhythmias are not understood and cannot be explained by a mechanism that relies solely on a dispersion of membrane properties that are observed in acute ischemia. This proposal seeks to test the hypothesis that abrupt changes int he macroscopic fiber structure serve as critical points in the formation of lines of block within reentrant circuits by redistributing currents and increasing the dispersion of recovery. The goal is to develop a predictive mechanism for arrhythmogenesis in tissue regions near a healing or healed infarct. A combined experimental/modeling approach will be used. High resolution epicardial potential mapping, using a custom 528 (22 x 24) channel electrode array with 1.1 mm spacing will be used to characterize a three-dimensional fiber structure in vivo and investigate its effect on activation wavefronts in normal porcine ventricular myocardium and in myocardium with pathways defined by cryoablation lesions. State-of-the-art realistic computer models of the myocardium that incorporate a full description of the complex fiber structure, tissue geometry and sophisticated membrane kinetic descriptions, will be used to test the hypothesis that nonuniformities in tissue structure affect the activation and recovery processes in different ways. The three-dimensional bidomain model will be validated for the first time by directly comparing activation and potential distributions arising from pacing. This validation will characterize the length scales for paced conduction and lead to quantitative analysis of such parameters as transmembrane potential and current flow that cannot be directly measured throughout the myocardium. The research will impact the ongoing development of new promising targeted therapies for arrhythmia management, such as cell transplantation or ablation. Both therapies can give rise to uncertain changes in the underlying fiber structure that could, if inappropriately applied, increase rather than decrease the possibility of sudden death.